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Probing human heart TCA cycle metabolism and response to glucose load using hyperpolarized [2-13 C]pyruvate MRS.
Chen, Hsin-Yu; Gordon, Jeremy W; Dwork, Nicholas; Chung, Brian T; Riselli, Andrew; Sivalokanathan, Sanjay; Bok, Robert A; Slater, James B; Vigneron, Daniel B; Abraham, M Roselle; Larson, Peder E Z.
Afiliação
  • Chen HY; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
  • Gordon JW; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
  • Dwork N; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
  • Chung BT; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
  • Riselli A; School of Pharmacy, University of California, San Francisco, California, USA.
  • Sivalokanathan S; Division of Cardiology, University of California, San Francisco, California, USA.
  • Bok RA; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
  • Slater JB; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
  • Vigneron DB; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
  • Abraham MR; Division of Cardiology, University of California, San Francisco, California, USA.
  • Larson PEZ; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
NMR Biomed ; 37(3): e5074, 2024 Mar.
Article em En | MEDLINE | ID: mdl-38054254
INTRODUCTION: The healthy heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2-13 C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2-13 C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility. METHODS: Good manufacturing practice [2-13 C]pyruvic acid was polarized in a 5 T polarizer for 2.5-3 h. Following dissolution, quality control parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5 cm axial slab-selective spectroscopy approach was prescribed over the left ventricle and acquired at 3 s intervals on a 3 T clinical MRI scanner. RESULTS: The study protocol, which included HP substrate injection, MR scanning, and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2-13 C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2-13 C]lactate, TCA-associated metabolite [5-13 C]glutamate, and [1-13 C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13 C-labeling of lactate, glutamate, and acetylcarnitine from 13 C-pyruvate increased by an average of 39.3%, 29.5%, and 114% respectively in the three subjects, which could result from increases in lactate dehydrogenase, pyruvate dehydrogenase, and CAT enzyme activity as well as TCA cycle flux (glucose oxidation). CONCLUSIONS: HP [2-13 C]pyruvate imaging is safe and permits noninvasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1-13 C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ácido Pirúvico / Miocárdio Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ácido Pirúvico / Miocárdio Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article